Lassa virus glycoprotein nanoparticles elicit neutralizing antibody responses and protection

Brouwer, Philip J.M.; Antanasijevic, Aleksandar; Ronk, Adam J.; Müller-Kräuter, Helena; Watanabe, Yasunori; Claireaux, Mathieu; Perrett, Hailee R.; Bijl, Tom P. L.; Grobben, Marloes; Umotoy, Jeffrey C.; Schriek, Angela I.; Burger, Judith A.; Tejjani, Khadija; Lloyd, Nicole M.; Steijaert, Thijs H; Haaren, Marlies M. van; Sliepen, Kwinten; Taeye, Steven W. de; Gils, Marit J. van; Crispin, Max; Strecker, Thomas; Bukreyev, Alexander; Ward, Andrew B.; Sanders, Rogier W.

doi:10.1016/j.chom.2022.10.018

Cited by 21 publications

(47 citation statements)

References 66 publications

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“…It has been reported that 58 million people are at risk of contracting LASV, with an estimated 100,000 to 300,000 cases and 5000 deaths per year in West Africa [ 1 ]. However, these numbers are likely to be underestimated due to the lack of appropriate diagnosis in poor areas such as rural areas and the non-specific febrile symptoms of Lassa fever [ 2 ]. Hospitalized LASV HF patients have a mortality rate of 15–20%, and survivors often suffer permanent damage to their bilateral hearing after surviving the infection [ 3 , 4 , 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Benzimidazole Derivatives as Potential Lassa Virus Inhibitors

Chen

Wang

et al. 2023

Molecules

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The Lassa virus (LASV) causes Lassa fever, a highly infectious and lethal agent of acute viral hemorrhagic fever. At present, there are still no effective treatments available, creating an urgent need to develop novel therapeutics. Some benzimidazole compounds targeting the arenavirus envelope glycoprotein complex (GPC) are promising inhibitors of LASV. In this study, we synthesized two series of LASV inhibitors based on the benzimidazole structure. Lentiviral pseudotypes bearing the LASV GPC were established to identify virus entry inhibitors. Surface plasmon resonance (SPR) was further used to verify the binding activities of the potential compounds. Compounds 7d−Z, 7h−Z, 13c, 13d, and 13f showed relatively excellent antiviral activities with IC50 values ranging from 7.58 to 15.46 nM and their SI values above 1251. These five representative compounds exhibited stronger binding affinity with low equilibrium dissociation constants (KD < 8.25 × 10−7 M) in SPR study. The compound 7h−Z displayed the most potent antiviral activity (IC50 = 7.58 nM) with a relatively high SI value (2496), which could be further studied as a lead compound. The structure–activity relationship indicated that the compounds with lipophilic and spatially larger substituents might possess higher antiviral activity and a much larger safety margin. This study will provide some good guidance for the development of highly active compounds with a novel skeleton against LASV.

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Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Benzimidazole Derivatives as Potential Lassa Virus Inhibitors

Chen

Wang

et al. 2023

Molecules

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“…27,28 Since then, methods have been described to stabilize the trimeric conformation of prefusion GPC in the absence of a trimer-stabilizing mAb. [29][30][31] We previously demonstrated that prefusion GPC trimers are stabilized by genetic fusion to the trimeric scaffold I53-50A. 30,31 These fusion proteins, known as GPC-I53-50A, have not only proven to be a useful reagent for characterizing and isolating GPC-specific antibodies but also were able to induce NAb responses in rabbits.…”

Section: Introductionmentioning

confidence: 99%

“…[29][30][31] We previously demonstrated that prefusion GPC trimers are stabilized by genetic fusion to the trimeric scaffold I53-50A. 30,31 These fusion proteins, known as GPC-I53-50A, have not only proven to be a useful reagent for characterizing and isolating GPC-specific antibodies but also were able to induce NAb responses in rabbits. 30,31 Protective immunity to LASV infection has been attributed to cell-mediated responses 5 with severe infections often associated with poor T-cell responses to the GPC and nucleoprotein.…”

Section: Introductionmentioning

confidence: 99%

“…30,31 These fusion proteins, known as GPC-I53-50A, have not only proven to be a useful reagent for characterizing and isolating GPC-specific antibodies but also were able to induce NAb responses in rabbits. 30,31 Protective immunity to LASV infection has been attributed to cell-mediated responses 5 with severe infections often associated with poor T-cell responses to the GPC and nucleoprotein. 14,32,33 NAb responses appear to play a limited role in curbing acute infection as they generally appear months after viral clearance.…”

Section: Introductionmentioning

confidence: 99%

“…vaccine 30 ; and virus-like particle vaccines. 51,52 While many of these have shown efficacy in animal models, induction of NAbs in most cases was absent or required numerous boosting immunizations.…”

Section: Introductionmentioning

confidence: 99%

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Defining bottlenecks and opportunities for Lassa virus neutralization by structural profiling of vaccine-induced polyclonal antibody responses

Brouwer,

Perrett,

Beaumont

et al. 2023

Preprint

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SummaryLassa fever continues to be a major public health burden in endemic countries in West Africa, yet effective therapies or vaccines are lacking. The isolation of potent and protective neutralizing antibodies against the Lassa virus glycoprotein complex (GPC) justifies the development of vaccines that can elicit strong neutralizing antibody responses. However, Lassa vaccines candidates have generally been unsuccessful in doing so and the associated antibody responses to these vaccines remain poorly characterized. Here, we establish an electron-microscopy based epitope mapping pipeline that enables high-resolution structural characterization of polyclonal antibodies to GPC. By applying this method to rabbits vaccinated with a recombinant GPC vaccine and a GPC-derived virus-like particle, we reveal determinants of neutralization which involve epitopes of the GPC-C, GPC-A, and GP1-A competition clusters. Furthermore, by identifying previously undescribed immunogenic off-target epitopes, we expose challenges that recombinant GPC vaccines face. By enabling detailed polyclonal antibody characterization, our work ushers in a next generation of more rational Lassa vaccine design.

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Influence of glycosylation on the immunogenicity and antigenicity of viral immunogens

Newby,

Allen,

Crispin

2024

Biotechnology Advances

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Lassa virus glycoprotein nanoparticles elicit neutralizing antibody responses and protection

Cited by 21 publications

References 66 publications

Design, Synthesis, and Biological Evaluation of Benzimidazole Derivatives as Potential Lassa Virus Inhibitors

Design, Synthesis, and Biological Evaluation of Benzimidazole Derivatives as Potential Lassa Virus Inhibitors

Defining bottlenecks and opportunities for Lassa virus neutralization by structural profiling of vaccine-induced polyclonal antibody responses

Influence of glycosylation on the immunogenicity and antigenicity of viral immunogens

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